Name: PROTAC EED degrader-1
Brand: BOC Sciences
Rating: 5 (1 reviews)

Size

Price

Stock

Quantity

$--

In stock

Purity

≥95%

Solubility

Soluble in DMSO

Storage

Store at -20°C

IUPACName

(2S,4R)-1-[(2S)-2-[[2-[4-[2-[3-[5-[5-[(5-fluoro-2,3-dihydro-1-benzofuran-4-yl)methylamino]-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl]-6-methylpyridin-2-yl]propanoylamino]ethoxy]phenoxy]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide

Synonyms

N-({4-[2-({3-[5-(5-{[(5-Fluoro-2,3-dihydro-1-benzofuran-4-yl)methyl]amino}[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-6-methyl-2-pyridinyl]propanoyl}amino)ethoxy]phenoxy}acetyl)-3-methyl-L-valyl-(4R)-4-hydroxy-N-[4-(4-methyl-1,3-thiazol-5-yl)benzyl]-L-prolinamide; L-Prolinamide, N-[2-[4-[2-[[3-[5-[5-[[(5-fluoro-2,3-dihydro-4-benzofuranyl)methyl]amino]-1,2,4-triazolo[4,3-c]pyrimidin-8-yl]-6-methyl-2-pyridinyl]-1-oxopropyl]amino]ethoxy]phenoxy]acetyl]-3-methyl-L-valyl-4-hydroxy-N-[[4-(4-methyl-5-thiazolyl)phenyl]methyl]-, (4R)-

Density

1.41±0.1 g/cm3

InChI Key

FSFJUWLIBSALJI-FENRPDQVSA-N

InChI

InChI=1S/C55H60FN11O8S/c1-32-40(43-27-60-54(67-30-62-65-51(43)67)59-26-42-41-20-22-74-46(41)18-17-44(42)56)16-10-36(63-32)11-19-47(69)57-21-23-73-38-12-14-39(15-13-38)75-29-48(70)64-50(55(3,4)5)53(72)66-28-37(68)24-45(66)52(71)58-25-34-6-8-35(9-7-34)49-33(2)61-31-76-49/h6-10,12-18,27,30-31,37,45,50,68H,11,19-26,28-29H2,1-5H3,(H,57,69)(H,58,71)(H,59,60)(H,64,70)/t37-,45+,50-/m1/s1

SMILES

CC1=C(C=CC(=N1)CCC(=O)NCCOC2=CC=C(C=C2)OCC(=O)NC(C(=O)N3CC(CC3C(=O)NCC4=CC=C(C=C4)C5=C(N=CS5)C)O)C(C)(C)C)C6=CN=C(N7C6=NN=C7)NCC8=C(C=CC9=C8CCO9)F

Mechanism

Target: Targets EED subunit of the PRC2 chromatin-repressive complex for experimental targeted protein degradation studies.

Binding Site: Binds the EED aromatic cage ligand pocket and recruited E3 ligase site to support productive ternary complex formation.

Mechanism of Action: PROTAC EED degrader-1 is designed for use in PROTAC or targeted protein degradation experiments directed toward EED subunit of the PRC2 chromatin-repressive complex. The bifunctional molecule links a target-recognition element to cereblon, promoting proximity between the protein of interest and ubiquitination machinery. Productive ternary-complex formation can drive polyubiquitination and proteasome-dependent target depletion, allowing researchers to compare pharmacological inhibition with protein removal. It is suitable for evaluating degradation potency, kinetics, pathway selectivity, and downstream signaling consequences in engineered or disease-relevant cellular models.

Applications

• PROTAC-Mediated EED Degradation: This application involves using PROTAC EED degrader-1 to selectively degrade the embryonic ectoderm development (EED) protein, a core component of the polycomb repressive complex 2 (PRC2). Researchers can explore the functional consequences of EED degradation on gene silencing and epigenetic regulation pathways.

• Epigenetic Modulation Studies: By employing PROTAC EED degrader-1, scientists can investigate the role of targeted protein degradation in modulating epigenetic landscapes. This approach aids in understanding how EED influences chromatin states and contributes to transcriptional repression in various cellular contexts.

• Cancer Biology Research: PROTAC EED degrader-1 is instrumental in studying the implications of EED degradation within oncogenic pathways. Researchers can analyze how disrupting PRC2 function affects tumor growth and progression, providing insights into potential therapeutic targets for cancer treatment.

• Mechanistic Pathway Analysis: Utilizing PROTAC EED degrader-1 allows for detailed examination of the mechanistic pathways involving EED. This facilitates the elucidation of downstream effects resulting from targeted protein degradation, offering potential avenues for novel drug discovery and development.

1. EED-targeted PROTACs degrade EED, EZH2, and SUZ12 in the PRC2 complex.

Hsu, J.H.R., Rasmusson, T., Robinson, J., Pachl, F., Read, J., Kawatkar, S., O'Donovan, D.H., Bagal, S., Code, E., Rawlins, P. and Argyrou, A., 2020. Cell chemical biology, 27(1), pp.41-46.

Deregulation of the PRC2 complex, comprised of the core subunits EZH2, SUZ12, and EED, drives aberrant hypermethylation of H3K27 and tumorigenicity of many cancers. Although inhibitors of EZH2 have shown promising clinical activity, preclinical data suggest that resistance can be acquired through secondary mutations in EZH2 that abrogate drug target engagement. To address these limitations, we have designed several hetero-bifunctional PROTACs (proteolysis-targeting chimera) to efficiently target EED for elimination. Our PROTACs bind to EED (pKD ~ 9.0) and promote ternary complex formation with the E3 ubiquitin ligase. The PROTACs potently inhibit PRC2 enzyme activity (pIC50 ~ 8.1) and induce rapid degradation of not only EED but also EZH2 and SUZ12 within the PRC2 complex. Furthermore, the PROTACs selectively inhibit proliferation of PRC2-dependent cancer cells (half maximal growth inhibition [GI50] = 49-58 nM). In summary, our data demonstrate a therapeutic modality to target PRC2-dependent cancer through a PROTAC-mediated degradation mechanism.

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